New N-Heterocyclic Carbene Ligand and Its Application in Asymmetric Nickel-Catalyzed Aldehyde/Alkyne Reductive Couplings

Abstract

Allylic alcohols are integral subunits of a variety of biologically interesting natural products as well as key building blocks for a number of important synthetic transformations. Among the numerous strategies for the preparation of allylic alcohols, the reductive coupling of aldehydes and alkynes in either an inter-or intramolecular sense arguably provides the most direct access to this important substructure from simple precursors. 1,2 Whereas several asymmetric approaches to the reductive coupling of aldehydes and alkynes have been reported, 3 our recent studies involving the use of achiral N-heterocyclic carbene complexes of nickel illustrated several important features including broad scope with both internal and terminal alkynes, direct incorporation of a silyl protecting group, and the ability to tune alkyne regioselection in macrocyclizations based on ligand sterics. 4 In order to capitalize upon these advantages, we have now examined the asymmetric coupling of aldehydes and alkynes using chiral N-heterocyclic carbene complexes.Pioneering studies from Grubbs illustrated that N-heterocyclic carbenes derived from C-2 symmetric diamines and mono-ortho-substituted aryl halides were excellent participants in asymmetric ring-closing metathesis reactions. 5 Members of this structural class of Nheterocyclic carbenes appeared to be promising candidates for asymmetric nickel-catalyzed reductive couplings. We thus examined the reductive coupling of benzaldehyde and 1-phenylpropyne under a variety of conditions to provide a lead ligand structure for further optimization. The known N-heterocyclic carbene ligands, generated in situ from 1a and 1b in THF with KO-t-Bu, allowed the production of the desired protected allylic alcohol 2a in modest yield and poor enantioselectivity (Table 1). New ligands 1c and 1d, which incorporate an ortho-phenyl or ortho-cyclohexyl substituent, were then prepared from the commercially available aryl bromides. A reaction involving ligand 1c afforded product 2a with slightly improved enantioselectivity, whereas a reaction with ligand 1d proceeded with significantly improved enantioselectivity, affording compound 2a in 76% ee in 60% yield. Despite the encouraging enantioselectivity with ligand 1d, examination of additional starting material combinations illustrated that yields were often poor to modest. Given the requirement of steric hindrance to stabilize free N-heterocyclic carbenes (by preventing dimerization), we next considered ortho,ortho-disubstituted carbene ligands. Ligand 1e was thus prepared, which did indeed allow improved chemical yields but with low enantioselectivities. Recognizing that ortho,ortho-disubstitution was optimal from the standpoint of chemical yield, whereas steric differentiation of the two ortho substituents was optimal from the standpoint of enantioselectivity, we next prepared ligand 1f. Under the same conditions described for the above experiments, chemical yields in couplings of benzaldehyde and 1-phenylpropyne jmontg@umich.edu. Supporting Information Ava...

Chiral ligand optimization in the asymmetric zirconium–zinc transmetalation aldehyde addition reaction

“…Asymmetric variants include the Nozaki-Hiyama-Kishi reaction employing a chiral sulfonamide ligand pioneered by Kishi et al, 6 Ni-catalyzed reactions using a chiral phosphine ligand introduced by Jamison et al 7 and an N-heterocyclic carbene ligand by Montgomery et al, 8 and an iridium-catalyzed hydrogenative coupling approach utilizing a chiral phosphoric acid derived from BINOL developed by Krische and Komanduri. 9 Alkenylzinc reagents can also be utilized to gain access to this functionality.…”

A Streamlined Strategy for Aglycone Assembly and Glycosylation

“…Couplings of cyclohexane carboxyaldehyde and 1-octyne with the sugar silane 1b derived from tribenzylglucosyl fluoride were examined utilizing the chiral N-heterocyclic carbene ligand 5 previously developed in our labs (Scheme 5). [10] As anticipated, sugar chirality played no role in stereoinduction, and the diastereomeric ratios for generation of the reductive coupling products 6a (from the R,R-5) and 6b (from S,S-5) were opposite and of very similar magnitude, with diastereoselectivities being governed by ligand chirality. Following procedures previously developed for intermolecular glycosylations of glycosyl fluorides, [11] intramolecular glycosylation of silyl-linked intermediates 6a and 6b afforded exclusively the α-gluco stereochemistry of the diastereomeric glycosidic linkages of glycosides 7a and 7b.…”

“…Couplings of cyclohexane carboxyaldehyde and 1-octyne with the sugar silane 1b derived from tribenzylglucosyl fluoride were examined utilizing the chiral N-heterocyclic carbene ligand 5 previously developed in our labs (Scheme 5). [10] As anticipated, sugar chirality played no …”

Palladium-catalyzed amination in the synthesis of polyazamacrocycles

“…The system Pd(0)/BINAP is widely used for the synthesis of various N,N′-diaryl-substituted 1,2-diamines as ligands for catalytic reactions with participation of copper and intermediates in the preparation of more complex molecules [45][46][47][48][49][50][51][52][53][54]. These works were published after our first publications on that topic.…”